IMPLEMENTATION & USE of IMPLEMENTATION & USE of CRRT in PEDIATRIC CRRT in PEDIATRIC

INTOXICATIONSINTOXICATIONS

Patrick D. Brophy MD Patrick D. Brophy MD

University of MichiganUniversity of Michigan

Pediatric NephrologyPediatric Nephrology

OBJECTIVESOBJECTIVES

Review pharmacokinetic propertiesReview pharmacokinetic properties

When to implement therapyWhen to implement therapy

Review extracorporeal techniques for toxin Review extracorporeal techniques for toxin removalremoval

Other factors involvedOther factors involved

Address Dr. Bulloch’s chosen ingestionsAddress Dr. Bulloch’s chosen ingestions

Future directions!!Future directions!!

IntroductionIntroduction

• 2.2 million reported poisonings (1998) 2.2 million reported poisonings (1998) 67% in pediatrics67% in pediatrics

• Approximately 0.05% required Approximately 0.05% required extracorporeal elimination extracorporeal elimination

• Primary prevention strategies for acute Primary prevention strategies for acute ingestions have been designed and ingestions have been designed and implemented (primarily with legislative implemented (primarily with legislative effort) with a subsequent decrease in effort) with a subsequent decrease in poisoning fatalitiespoisoning fatalities

Options & PharmacokineticsOptions & Pharmacokinetics

Extracorporeal MethodsExtracorporeal Methods– Peritoneal DialysisPeritoneal Dialysis– HemodialysisHemodialysis– HemofiltrationHemofiltration– Charcoal hemoperfusionCharcoal hemoperfusion

ConsiderationsConsiderations– Volume of Distribution (Vd)/compartmentsVolume of Distribution (Vd)/compartments– molecular sizemolecular size– protein/lipid bindingprotein/lipid binding– solubilitysolubility

PharmacokineticsPharmacokinetics

GENERAL PRINCIPLESGENERAL PRINCIPLES– kinetics of drugs are based on therapeutic not kinetics of drugs are based on therapeutic not

toxic levels (therefore kinetics may change)toxic levels (therefore kinetics may change)– choice of extracorporeal modality is based on choice of extracorporeal modality is based on

availability, expertise of people & the properties availability, expertise of people & the properties of the intoxicant in generalof the intoxicant in general

– Each Modality has drawbacksEach Modality has drawbacks– It may be necessary to switch modalities during It may be necessary to switch modalities during

therapy (combined therapies inc: endogenous therapy (combined therapies inc: endogenous excretion/detoxification methods) excretion/detoxification methods)

PHARMOCOKINETIC COMPARTMENTS

kidney

blood

Peripheral

liver

GI TractDistribution Re-distribution

INPUT

ELIMINATION

PharmacokineticsPharmacokinetics

Volume of Distribution (Vd)Volume of Distribution (Vd)

Mathematical construct referring to the Mathematical construct referring to the volume a toxin/drug would occupy if the volume a toxin/drug would occupy if the body were a single homogenous vessel in body were a single homogenous vessel in which toxin and plasma concentration which toxin and plasma concentration were equalwere equal

A large Vd has been arbitrarily defined as A large Vd has been arbitrarily defined as >0.6 l/kg (the total body water space)>0.6 l/kg (the total body water space)– Vd= Amount in the body/plasma concentrationVd= Amount in the body/plasma concentration

Binding To Circulating ProteinsBinding To Circulating Proteins

Albumin- primary culpritAlbumin- primary culprit

Generally only unbound toxin/drug is available Generally only unbound toxin/drug is available for metabolism, excretion & elimination by CRRTfor metabolism, excretion & elimination by CRRT– In overdose-protein saturation may be 100%, so In overdose-protein saturation may be 100%, so

free drug/toxin exists that is amenable to removal!free drug/toxin exists that is amenable to removal!

Binding altered by:Binding altered by:Uremic Toxin Retention; pH; hyperbilirubinemiaUremic Toxin Retention; pH; hyperbilirubinemia

Drug displacement, heparin, free fatty acidsDrug displacement, heparin, free fatty acids

Molar ratio of drug/toxin to proteinMolar ratio of drug/toxin to protein

Other Properties Altering CRRT Other Properties Altering CRRT RemovalRemoval

Gibbs-Donnan effect – drug chargeGibbs-Donnan effect – drug charge

Molecular weightMolecular weight

Membrane Binding (Adsorption)-AN69Membrane Binding (Adsorption)-AN69

Membrane PropertiesMembrane Properties– Solute pore sizeSolute pore size– Hydraulic PermeabilityHydraulic Permeability– Surface AreaSurface Area

When To Implement TherapyWhen To Implement Therapy

INDICATIONSINDICATIONS– >48 hrs on vent>48 hrs on vent– ARFARF– Impaired Impaired

metabolismmetabolism– high probability of high probability of

significant significant morbidity/mortalitymorbidity/mortality

– progressive clinical progressive clinical deterioration deterioration

INDICATIONSINDICATIONS– severe intoxication severe intoxication

with abnormal vital with abnormal vital signs signs

– complications of complications of coma coma

– prolonged coma prolonged coma – intoxication with an intoxication with an

extractable drugextractable drug

OptionsOptions

PERITONEAL DIALYSISPERITONEAL DIALYSIS– 1st done in 1934 for 2 anuric patients after 1st done in 1934 for 2 anuric patients after

sublimate poisoning sublimate poisoning (Balzs et al; Wien Klin Wschr 1934;47:851 )(Balzs et al; Wien Klin Wschr 1934;47:851 )

– Allows diffusion of toxins across peritoneal Allows diffusion of toxins across peritoneal membrane from mesenteric capillaries into membrane from mesenteric capillaries into dialysis solution within the peritoneal cavitydialysis solution within the peritoneal cavity

– limited use in poisoning (clears drugs with low limited use in poisoning (clears drugs with low Mwt., Small Vd, minimal protein binding & Mwt., Small Vd, minimal protein binding & those that are water soluble) those that are water soluble)

alcohols, NaCl intoxications, salicylatesalcohols, NaCl intoxications, salicylates

OptionsOptions

HEMODIALYSISHEMODIALYSIS– optimal drug characteristics for removal:optimal drug characteristics for removal:

relative molecular mass < 500 relative molecular mass < 500

water solublewater soluble

small Vd (< 1 L/Kg)small Vd (< 1 L/Kg)

minimal plasma protein bindingminimal plasma protein binding

single compartment kineticssingle compartment kinetics

low endogenous clearance (< 4ml/Kg/min)low endogenous clearance (< 4ml/Kg/min)(Pond, SM - Med J Australia 1991; 154: 617-622)(Pond, SM - Med J Australia 1991; 154: 617-622)

OptionsOptions

Intoxicants amenable to HemodialysisIntoxicants amenable to Hemodialysis– vancomycin (high flux)vancomycin (high flux)– alcoholsalcohols

diethylene glycoldiethylene glycol

methanolmethanol

– lithiumlithium– salicylatessalicylates

OptionsOptions

High Flux Dialysis forVancomycin Overdose

0

50

100

150

200

250

0 3 15 18 30 33

Vanco Level (ug/ml)

CHARCOAL HEMOPERFUSIONCHARCOAL HEMOPERFUSION– optimal drug characteristics for removal:optimal drug characteristics for removal:

Adsorbed by activated charcoalAdsorbed by activated charcoal

small Vd (< 1 L/Kg)small Vd (< 1 L/Kg)

single compartment kineticssingle compartment kinetics

protein binding minimal (can clear some highly protein binding minimal (can clear some highly protein bound molecules) protein bound molecules)

low endogenous clearance (< 4ml/Kg/min)low endogenous clearance (< 4ml/Kg/min)(Pond, SM - Med J Australia 1991; 154: 617-622)(Pond, SM - Med J Australia 1991; 154: 617-622)

OptionsOptions

High Flux Dialysis forTegretol Overdose

0

5

10

15

20

25

30

35

OptionsOptions

Intoxicants amenable to Charcoal Intoxicants amenable to Charcoal HemoperfusionHemoperfusion– Carbamazepine (also high flux HD)Carbamazepine (also high flux HD)– phenobarbital (also High flux HD)phenobarbital (also High flux HD)– phenytoin (also High Flux HD)phenytoin (also High Flux HD)– Valproic Acid (CVVHDF) Valproic Acid (CVVHDF) Minari et.al. Annals of Emer Med 39:2002Minari et.al. Annals of Emer Med 39:2002

– theophyllinetheophylline– Paraquat (poor clearance with all current Paraquat (poor clearance with all current

therapies) –HP+CVVH prolonged survivaltherapies) –HP+CVVH prolonged survivalKoo et.al. Koo et.al.

AJKD 39:2002AJKD 39:2002

OptionsOptions

OptionsOptions

HEMOFILTRATIONHEMOFILTRATION– optimal drug characteristics for removal:optimal drug characteristics for removal:

relative molecular mass less than the cut-off of the relative molecular mass less than the cut-off of the filter fibres (usually < 40,000)filter fibres (usually < 40,000)

small Vd (< 1 L/Kg)small Vd (< 1 L/Kg)

single compartment kineticssingle compartment kinetics

low endogenous clearance (< 4ml/Kg/min)low endogenous clearance (< 4ml/Kg/min)(Pond, SM - Med J Australia 1991; 154: 617-622)(Pond, SM - Med J Australia 1991; 154: 617-622)

OptionsOptions

Continuous Detoxification methodsContinuous Detoxification methods

CAVHF, CAVHD, CAVHDF, CVVHF, CAVHF, CAVHD, CAVHDF, CVVHF, CVVHD, CVVHDFCVVHD, CVVHDF

Indicated in cases where removal of Indicated in cases where removal of plasma toxin is then replaced by plasma toxin is then replaced by redistributed toxin from tissueredistributed toxin from tissue

Can be combined with acute high flux HDCan be combined with acute high flux HD

OptionsOptions

0

1

2

3

4

5

6Pt #1Pt #2

Hours

Li

mEq/ L

CVVHD following HD for Lithium poisoning

HD started

CVVHD started CT-190 (HD)Multiflo-60both patientsBFR-pt #1 200 ml/minHD & CVVHD -pt # 2 325 ml/minHD & 200 ml/min

CVVHDPO4 Based dialysate at

2L/1.73m2/hr

Li Therapeutic range0.5-1.5 mEq/L

OptionsOptions

Intoxicants amenable to HemofiltrationIntoxicants amenable to Hemofiltration– vancomycinvancomycin– methanolmethanol– procainamideprocainamide– hirudinhirudin– thalliumthallium– lithiumlithium– methotrexatemethotrexate

OptionsOptions

Plasmapheresis / Exchange Blood Plasmapheresis / Exchange Blood TransfusionsTransfusions– Plasmapheresis Plasmapheresis (Seyffart G. Trans Am Soc Artif Intern Organs (Seyffart G. Trans Am Soc Artif Intern Organs

1982; 28:673)1982; 28:673)

role in intoxication not clearly establishedrole in intoxication not clearly established

most useful for highly protein bound agentsmost useful for highly protein bound agents

– Exchange Blood TransfusionsExchange Blood TransfusionsPediatric experience > than adultPediatric experience > than adult

MethemoglobinemiaMethemoglobinemia

overall very limited role in poisoningoverall very limited role in poisoning

Other IssuesOther Issues

Optimal prescriptionOptimal prescription

Biocompatible filters - may increase Biocompatible filters - may increase protein adsorptionprotein adsorption

Maximal blood flow rates (ie good access)Maximal blood flow rates (ie good access)

Physiological solution (ARF vs non ARF)Physiological solution (ARF vs non ARF)

? Removal of antidote? Removal of antidote

Counter-current D maximal removal of Counter-current D maximal removal of toxins (CVVHDF?)toxins (CVVHDF?)

Dr. Bulloch’s OverdosesDr. Bulloch’s Overdoses

Sulfonylureas-low MW, low PB, high renal Sulfonylureas-low MW, low PB, high renal excretion- YES to HFexcretion- YES to HF

CCB’s-high PB, large Vd, poor removal-CCB’s-high PB, large Vd, poor removal-possible if proteins saturatedpossible if proteins saturated

Ethylene Glycol/Methanol- YESEthylene Glycol/Methanol- YES

BZD’s-high PB, large Vd, poor removalBZD’s-high PB, large Vd, poor removal

Iron-difficult due to protein binding-likely Iron-difficult due to protein binding-likely can dialyze Fe+deferoxamine complexcan dialyze Fe+deferoxamine complex

Future DirectionsFuture Directions

Liver Assist DevicesLiver Assist Devices– Albumin dialysis with anionic and charcoal Albumin dialysis with anionic and charcoal

recharge filtersrecharge filters– Can use a variety of hemofilters and perform Can use a variety of hemofilters and perform

CVVH, CVVHD, CVVHDFCVVH, CVVHD, CVVHDF– Will begin looking at intoxications with this Will begin looking at intoxications with this

device in Michigan in 2003device in Michigan in 2003

ACKNOWLEDGEMENTSACKNOWLEDGEMENTS– MELISSA GREGORYMELISSA GREGORY– ANDREE GARDNERANDREE GARDNER– JOHN GARDNERJOHN GARDNER– THERESA MOTTESTHERESA MOTTES– TIM KUDELKATIM KUDELKA– LAURA DORSEY & BETSY ADAMSLAURA DORSEY & BETSY ADAMS

(p. brophy)